ABSTRACT Avian influenza viruses (AIVs) are associated with more severe disease but less transmissibility after infection of humans than are seasonal influenza viruses. Animal models and limited studies of single or small clusters of AIV human cases have been utilized to understand the underlying mechanisms with varying success and inference. Hampering scientific progress to a substantial degree has been the historically sporadic nature of human AIV cases, making comparative and extensive prospective studies unfeasible. The emergence of the H7N9 AIV in China has now changed this. These H7N9 cases are associated with a predictable spatial and temporal pattern that makes it feasible to consider a cohort study. Here, we propose to conduct a longitudinal study to identify the immunological and virological hallmarks of AIV infections in humans. Our study will test two hypotheses: 1) severe disease caused by H7N9 AIVs is a consequence of a lack of early cross- protective CD8+ T-cell responses, and, 2) replication of AIVs in the mammalian host limits virus population diversity which in turn limits onwards transmission. Southern China is a particularly important region for human cases of AIV due to its high density of humans and domestic poultry. Our proposed study site at the First Affiliated Hospital of Guangzhou Medical University, which is also a designated National Reference Center for Respiratory Diseases, is perfectly suited for this study. The completion of the above aims will lead to the most comprehensive analysis of AIV infections in humans to date and also to a direct side-by-side comparison with seasonal influenza. Critical cross training of US and Chinese scientists will also be a major milestone leading to improved global public health research capacity.